Method of treating prostatic hypertrophy

ABSTRACT

Orally administered compositions for treating prostatic hypertrophy are described herein, these compositions containing an effective dose of a pharmaceutical formulation comprising filipin, a polyenic macrolide. Also the method of treating prostatic hypertrophy with such compositions, is described herein.

United States Patent [1 1 [111 3,721,734 Gordon 51March 20, 1973 METHODOF TREATING PROSTATIC [56] References Cited HYPERTROPHY '75] I. H, W C dN Y k N Y OTHER PUBLICATIONS to n w 0 r e r Merck Index, 8th Edition,1968, Merck & Co., Inc., [73] Assignee: Julius Schmid Inc.,New York,N.Y.'Rahway, NJ. page 458 (Abstract Weissman, Drug Trade News July 4, 1966p. 40) Chemical Abstracts [22] Filed: Oct. 29, 1971 69 75500 19 [21]Appl.N0.: 194,052

Primary Examiner-Jerome D. Goldberg Related US. Application DataAttorney-Darby & Darby [60] Division of Ser. No. 70,509, Sept. 8, 1970,which is a continuation-in-part of Ser. No. 544,712, April 25, [57]ABSTRACT 1966 abandmed and a cntinuatin of Orally administeredcompositions for treating pro- 623847Mamh 1967 static hypertrophy aredescribed herein, these compositions containing an effective dose of apharmaceu- [52] US. Cl. ..424/278, 424/117, 424/118, tica] formulationcomprising filipin a polyenic macro 424/120 424, l2l'424/122 lide. Alsothe method of treating prostatic hyper- 3 Claims, No Drawings such assteroids. However, the treatment with steroids or other hormones isseverely restricted since its effect is related to the suppression ofthe secretion of a gonadotropic substance by the adrenal cortex.Further, the administration of a hormone carries with it extensivephysiological effects on the organ and organ systems in addition to theprostate. Therefore, there has not been availablea composition for thetreatment of prostatic hypertrophy which has a broad spectrum ofeffectiveness independent of the cause of the prostatic hypertrophy.

A great number of polyenic macrolide antibiotic compounds are knowntoday which are used or proposed for use as antifungal chemotherapeuticagents and which have been the subject of extensive scientificinvestigation in past years. Biologically, the polyene macrolideantibiotics have been recognized to be potent chemotherapeutic agentsagainst a wide variety of yeasts and fungi. However, the use of thesepolyenic macrolide compounds for the treatment of certain fungalinfections has been limited by their poor oral absorption from thegastrointestinal tract. The-application of'these polyenic macrolideantibiotic compounds has been restricted primarily to topical use.

It has now been unexpectedly discovered that the oral administration ofa filipin, a polyenic macrolide, composition has a selective effect onthe prostate gland in mammals which does not appear to express itseffect by stimulating or suppressing hormonalproducing endocrine glands.Its effect on the prostate is carried out by reducing its size andaltering its 'hypertrophic histological picture and texture to that of anormal appearing gland. This effect is believed not due to theantibiotic function of these polyenic macrolide compounds but apparentlyto their chemical structure.

Accordingly, one aspect of the present invention is to provide a methodfor the treatment of prostatic hypertrophy which comprises orallyadministering an effective does of filipin a specific known polyenicmacrolide compound. Another aspect of the present invention is to.provide an orally administered compositionfor the treatment of prostatichypertrophy which composition comprises a pharmaceutical formulationcomprising an effective does of filipin a specific known polyenicmacrolide compound.

Anadditional aspect of the present invention isto provide an enterictablet or capsule containing an effective dose of a composition of thepresent invention for the treatment of prostatic hypertrophy.

Other aspect of the invention will be apparent g from the followingdetailed description.

According to the present invention, the compositions found effective forthe treatment of prostate hypertrophy in mammals comprise filipin, apolyenic macrolide composition. Since the polyenic compounds were firstdiscovered in 1950, a large body of literature has become availabledescribing the extensive chemical investigation of these compounds anddemonstrating that they possess generally similar chemical properties.The present broad classification of the polyenic macrolide compounds isdue to the work of Oroshnik et al., in 1955 (see Polyene Antibiotics,Science, Vol. 121, pp. 147-149). In 1955 only nine polyenic macrolidecompounds had been isolated in reasonably pure form but since then wellover fifty polyenic macrolide compounds have been reported. Undoubtedlysome of these polyenes have been reported more than once under differentnames. The known polyenic macrolide compounds have been produced asantibiotics by cultivation of Streptomyces in different media and byextraction of the substances from these cultures. It has beendemonstrated in the literature that the known polyenic compounds are (l)of fairly high molecular weight (ca. 700-1500), (2) contain macrocyliclactones, better known as macrolides (hereinafter referred to aspolyenic macrolide compounds), and (3) each possess a chromophore in thenucleus of fnom four to seven conjugated double bonds(tetraenes,-pentaenes, hexaenes, and heptaenes) identified byexamination of their ultra-violet absorption spectra. These conjugatedsystems are generally unsubstituted (except the methyl pentaenes) andeither of the all-trans" or cis-trans configuration. Based on theevidence available to date, it is indicated that the known polyenicmacrolide compounds contain a twenty-six to a thirty-seven memberedlactone ring wherein all of the ring atoms except the single oxygen atomare carbons. The evidence to date also indicates that only C, H, O, andN are present in the known polyenic macrolide compounds.

The following articles should be consulted for references to thediscovery, isolation and chemical properties of the polyenic macrolidecompounds:

l. Vining, The Polyene Antifungal Antibiotics" Hindustan AntibioticsBull., Vol. 3, pp 32-54 (1960).

2. Waksman et al., The Actinomycetes, Vol. III,

Antibiotics of Actinomycetes (Williams and Wilkins, Baltimore, 1962).

3. Droughet, Noveaux Antibiotiques Antifongiques Symp. Int.Chimiotherapie, Naples, 1961, pp 21-50 (1963).

4. W. Oroshnik et al, Fortschritte der Chemie Organischer NaturstoffeVol. XXI, pp 18-79 chromophore), at least one hydroxyl moiety linked tothe nucleus and at least one substituent selected from the classconsisting of a single amino sugar moiety (mycosamine) glycosidicallylinked to the macrolide nucleus, carboxyls, methyls, carbonyls,aliphatics and hydroxy aliphatics. Representative of this group areeurocidin (same as seligocidin), fungichromatin, aliomycin, capacidin,distomycin B, antibiotic PA153, antibiotic No. 83, antibiotic No. 90,antibiotic 2814-1, St. effluvius pentaene and antibiotic A228.

Group ll Methyl Pentaenes:

Identified as those compounds containing a pentaene macrolide nucleushaving a methyl substituent located on a terminal bond of the all-transpentaene chromophore. Almost all of the methyl pentaenes are devoid ofany carboxyl and nitrogen containing'moieties. The only methyl pentaenewhich has been found to contain both an amino and carboxyl group ismoldcidin A. Most of these materials are neutral and contain manyhydroxyl groups e.g., ten in fungichromin). Other substituents such asaliphatic groups, hydroxy-aliphatic and carbonyls may be linked to themethyl pentaene macrolide nucleus. Representative of the methylpentaenes are fungichromin, filipin, durhamycin, lagosin (syn. glaxoantibiotic A-246), eurocidin group antibiotic, pentamycin, streptomycessanguineus methyl pentaene, cabicidin, moldcidin A and pentafungin.

It will be understood that where a polyenic macrolide compound of theclass herein described is identical with one of the above namedcompounds, but has been known by another name by reason of independentproduction or production in accompaniment to other antibiotics, theidentification of such substances by the name set forth above isintended to mean the same compound under all other designations.

in the preparation and administration of dosages, a variety ofpharmaceutical formulations may be employed, such as capsules, ortablets, preferably in enteric form. The quantity of effective dosesupplied by each capsule or tablet is relatively unimportant since thetotal dosage can be reached by administration of either one or aplurality of capsules or tablets or both. The capsules employed maycompose any well known pharmaceutically acceptable material, such asgelatin, cellulose derivatives, etc. The tablets may be formulated inaccordance with conventional procedure employing solid carriers,lubricants, etc., well known in the art. Examples of solid carriers are:starch, sugar, bentonite and other commonly used carriers.

The following examples illustrate suitable pharmaceutical formulationscontaining the compounds of this invention.

EXAMPLE 1 Hard gelatin capsule available from the Robin PharmacalCorporation (size is filled with about 0.83 grams of lactose (Fast Flowavailable from Foremost Dairies, Inc.) and about 100 mg. of activematerial, the lactose and active ingredient being triturated together ina pestle and mortar until a very fine yellow amorphous powder resulted,prior to filling of the capsule. Obviously, any desired number ofcapsules may be filled by mixing together any amount of lactose andactive ingredient in the same weight ratio indicated above so that eachcapsule will contain 100 mg. active ingredient; and the quantity ofactive ingredient may be altered, as desired, by varying the weightratio of the indicated materials.

EXAMPLE 2 g. of corn starch and 21 12.5 g. lactose are dried at F for 12hours before compounding. After drying, each of these materials issifted through a No. 14 mesh stainless steel screen. The sifted cornstarch and lactose are thoroughly mixed for 30 minutes and to thismixture there is added a blended mixture of 250 g. active ingredient and12.5 g. magnesium stearate. This admixture is blended and thencompressed on a tableting machine into 5000 substantially round tabletseach containing 50 mg. active ingredient and weighing about 500 mg.

EXAMPLE 3 Enteric tablets for use in this invention may be formulated asfollows:

16 g. of powdered corn starch (U.S.P. quality) is dried at 120F for 12hours and passed through a No. 25 mesh stainless steel screen. Thesifted corn starch is then mixed with 255 g. of anhydrous lactose(direct tablet grade). To this mixture, 4 g. of magnesium stearate isadded followed by 50 g. of the active ingredient. These materials arethen mixed in a small pebble mill for 30 minutes and compressed on asingle punch machine producing 1,000 tablets, each containing 50 mg.active ingredient. Each tablet weighs approximately 325 mg. The averagehardness is 6, as measured on a Monsanto Hardness Tester.

The tablets are then placed in a coating pan rotating at 29 rpm. andsubjected to warm air of approximately 80 F for about 10 minutes. Then30 ccs of a pharmaceutical glazed composition is applied, thiscomposition being refined wax and rosin free orange flake shellac withanhydrous alcohol as the medium therefor. Talcum (U.S.P.) or similardusting powder is applied to the tablets to prevent the tablets fromsticking to each other or to the pan and this procedure is followedafter the application of each coat to the tablets. The coat is allowedto dry for approximately one hour. Thereafter three additional coats areapplied in a similar manner, each coat comprising 30 ccs of thepharmaceutical glaze, with approximately one hour of drying time betweenthe application of successive coats. After four coats are applied thetablets are dried overnight at room temperature and then four more coatsare applied in the same manner using the same composition. Each coat isallowed to air dry for 3 hours before applying the next coat. Each ofthe 8 coats of the enteric tablets is approximately 0.001 inch inthickness. Obviously, the thickness of the coating can be controlled byvarying the concentration of the pharmaceutical glaze in the alcoholmedium.

The enteric tablets are tested in accordance with the in vitrodisintegration test for enteric-coated tablets described in U.S.P. XVlland were found to pass this test.

While the number of coats used in the example heretofore described is 8,it will be appreciated that there are many factors to be consideredwhich permit variation in the number of coats, including the size andshape of the tablets or capsules, the type of coat or combination ofcoats, etc.

on an altered dose of candicidin to determine whether increase of thedrug dose or discontinuance of dosage would further affect prostatesize. The remaining six dogs were sacrificed and autopsied aftercompletion of the administration of candicidin. The four dogs on which asecond laparotomy was performed were autopsied after completion of theadministration of candicidin for the period specified in the abovetable.

At the time of the second laparotomy and at necropsy the prostate glandwas measured and biopsy specimens of the prostate gland of each dog weretaken, with the exception of the three dogs indicated in the table forwhich no biopsy specimens were taken.

In addition, at necropsy, histologic specimens were taken of the generalorgans prostate, bladder, pancreas, kidney, adrenal, liver, spleen,testes, intestines,

4 caecum, lung, thyroid and heart for further microscophistologic studyof the organs listed did not reveal any evidence of drug toxicity.

At necropsy, blood and urine samples were obtained for assay. The assaymethod was essentially the procedure described for the assay ofNystatin-Candicidin in Assay Methods of Antibiotics 1955, a laboratorymethod, Donald C. Grove and William D. Randall, pp. 116-419: Method 2.The samples of dog serum and urine investigated microbiologically showedno antifungal activity. The assay tests establish the absence ofcandicidin in the blood and urine of the test animals.

As shown in the above table, the trauma induced by taking of a biopsy ofthe prostate gland was not the cause of the reduction in the size of theprostatic tissue. The gross appearance and measurements of the prostategland taken prior to the administration of candicidin and atlaparotomies performed after the drug had been administered revealed amarked reduction of the size of the prostate gland and normalconsistency of the gland which is consistent with a significantlyyounger age of dog. Microscopic examination of the biopsy specimens ofthe prostate gland on each dog taken at each of the surgical proceduresperformed confirmed the gross observation of normal appearance and asubstantial reduction of size.

The histologic evaluation of the prostate biopsies of dogs taken priorto candicidin administration and at laparotomies did not reveal anycytotoxicity in the gland. The enlarged prostate gland prior to drugadministration is characterized by considerable epithelial tufting orpapillation; cells are tall, columnar with granular cytoplasm, and glandacini are compressed. The marked reduction in the size of the prostategland after candicidin administration is accompanied by a decrease inthe size of the columnar epithelial cells which are mostly cuboidal;diminished or absent granularity; and papillations are reduced orabsent.

As indicated in the above table, body weight loss does not appear to berelated in any quantitive way to the dose of the drug administered sincethe dogs that received 100 mg/day showed a body weight loss no less orgreater than those animals receiving a higher dosage. The data also showthat a short time of administration, as noted with dog No. 8 of arelative high dose, 300 mg daily, for five days, effected a significantreduction in size of the prostate gland. In the case of dog No. 2,candicidin administration was discontinued after the second laparotomyas indicated in the table and after an additional 20 days of absence ofdrug administration, it was found that the prostate gland began toincrease in size and had achieved about a percent return towards thevolume noted at the start of the experiment. However, in this dog theprostate gland was not initially pathologically enlarged.

In some of the dogs diarrhea and vomiting occurred upon the oraladministration of candicidin but these effects appeared to be overcomewhen the dogs were fed a supplement of vitamin B-complex andlacto-bacilli.

Similar tests were conducted on dogs using nystatin (a tetraene). Thegross appearance and measurements of the prostate gland taken prior tothe administration of nystatin and at laparotomies performed after thedrug had been administered also revealed a reduction in size of theprostate gland but to a lesser extent than the candicidin treated dogsOther tests conducted with polyenic macrolide compounds in mammalsappear to indicate that the larger the chromophore in the macrolidenucleus the more effective is the compound in treating prostatichypertrophy. Accordingly, the. heptaene macrolide compounds arepreferably used because they have been found to generally give the bestresults whereas the tetraene macrolide compounds, generally, are leasteffective in reducing the size of the prostate gland.

It is also indicated that cleavage or other alteration of the macrolidenucleus which opens the lactone ring will destroy the activity of thecompounds as will alteration of the chromophore present in the nucleusby total hydrogenation.

Tests conducted with various polyene macrolide compounds includingfilipin, amphotericin B and fungimycin, indicate that the side chaingroups commonly found in the polyenic macrolide compounds are notessential to activity for treating prostate hypertrophy.

It is preferred, commensurate with the desideratum of obtaining thehighest degree of effectiveness of the compositions of this inventionper given dose of active ingredient, to use an enteric tablet orcapsule. Thus when using a specific known polyene macrolide compound inthe form of an enteric solid, the entire com-. pound will remain intactwhen it reaches the intestinal tract so long as the enteric coatingcomposition retains its integrity in the stomach. On the other hand,administration of the same does in a standard solid pharmaceuticalformulation may result in a cleavage of any amino sugar present, or ofother groups similarly sensitive to gastric conditions. Such cleavagemay further result in alteration of the polyenic macrolide nucleus,thereby diminishing the effectiveness of the active ingredient.

The effective dosage of the compounds of this invention depends upon theseverity of condition, the stage and the individual characteristics ofeach mammal being treated. It is expected that the compositions willgenerally be administered in a dosage range from about 1 mg to about mgactive ingredient per kg of body weight per day and preferably fromabout 5 mg to about 40 mg per kg of body weight per day.

What is claimed is:

Other procedures and materials well known in the prior art may beemployed to prepare suitable enteric coatings. The selection of thecoating substance is governed to a large extent by pH and enzymeconsiderations and the desire to have the enteric compositiondisintegrate or dissolve when it reaches the duodenum region of theintestinal tract and not in the stomach. The disintegration ordissolution of an enteric coating in the intestinal tract usuallydepends on several factors, the most important of which are (I) thepresence of acidic groups in the enteric substance which cause it to beinsoluble in the low pH environment of the stomach but soluble in theintestinal tract due to the higher (but usually not alkali) pH of themedia there, and (2) the resistance of the coating to attack by oral andgastric enzymes.

Illustrative of other well known substances that may be used for theenteric coating are the following: cellulose acetate phthalate withresinous carrier; cellulose acetate phthalate-tolu balsam-shellac;cellulose acetate phthalate with fats and waxes; shellac-Castor oil;ammoniated shellac; shellac-stearic acid-tolu balsam; stearicacid-castor oil over shellac-silica gel, cellulose acetate phthalateswith or without plasticizer and dusting powder(s); acid phthalates ofglucose, fructose, etc; ternary copolymers of styrene, methacrylic acidand butyl half-ester of maleic acid; alkyd resin-unsaturated fattyacids-shellac; polyvinyl acid phthalate, etc.

For a description of the procedure for manufacturing entericformulations such as those exemplified heretofore, reference should bemade to US. Pat. Nos. 2,196,768; 2,433,244; 2,455,790; 2,540,979;2,858,252; 3,080,346 and British Pat. Nos. 760,403 and 820,495.

The effectiveness of the compounds of this invention in treatingprostatic hypertrophy has been confirmed by tests in large mammals,i.e., those weighing at least about 1 kilogram. For example, tests wereconducted on dogs to demonstrate the effectiveness of the polyenicmacrolide compounds in reducing the size of the prostate gland.

Each dog was examined for the gross presence of prostatic hypertrophy bypalpation. All of the dogs, with the exception of two, were at least tenyears of age. The dogs were housed under kennel conditions for a weekprior to the oral administration of candicidin. During theacclimatization period the dogs become adjusted to the feeding andkennel routine. A thorough examination of the dogs, includingelectrocardiography, was undertaken during the acclimatization period.Four of the dogs exhibited a cardiac condition, not unusual for olderdogs, which was confirmed by electrocardiography and subsequently atnecropsy. This cardiac condition did not affect the course of theexperimental trial and indeed was helpful in establishing that even inthe presence of such a condition candicidin may be safely administered.

After the one week acclimatization period, a surgical laparotomy wasperformed on each of the dogs under general anesthesia. The prostategland was measured in three dimensions, lateral, cranial-caudal anddorsalventral and was palpated to determine its consistency. Visualobservation of the bladder, intestines, the caudal pole of the kidney,and spleen were made, and the palpation of the liver and kidney wasaccomplished. In all but three of the dogs a punch biopsy of theprostate was taken. The biopsy specimen taken from the left hemisphereof the prostate gland was fixed in formalin for histological andmicroscopic examination. The omission of a biopsy in three dogs wasinstituted as a control to determine whether the trauma of taking thebiopsy of the prostate gland might have some influence on inflammationand size of prostatic tissue. In addition, blood and urine specimenswere taken for candicidin assay and routine examination.

The dogs were permitted to recover from the surgical laparotomyfollowing which each of the dogs was placed on a regimen of oraladministration of candicidin in accordance with the schedule of doseadministration given in Table I below. The drug was administered in ahard gelatin capsule in the animal feed.

TABLE I Percent Prostate size decrease Animal in gland Daily bodyCranialsize from Dog Age dosage Dose weight Lateral caudal DorsalinitialNo. Procedure (years) (mg.) (days) (lbs) (mm.) (mm.) ventral volume 1stlaparotomy... 53 45 35 1 2nd laparotomy... 10-13 100 30 40 35 Autopsy200 20 41 42 1st lapar0t0my 25 20 20 2. 4 100 30 20 17 I7 "0 20 20 171'1 R .211 30 3 13 "I00 30 44 26 50 "400 14 3G .20 2'1 1st laparotomy".7. 50 so 4 2nd laparotomy... 10 30 ()1 41 3) Autopsy G00 14 50 35 .5)11st laparotomy....l 32 40 40 """|Antops i i "00 30 20 34 r, r listhiparot0my m i 3H 37 30 lAntopsy .J 300 so 25 34 .45 x j 33 37 2t Jun:50 2s 27 L w so no 50-55 300 5 5) 45-50 .lo 4 42 .i t 300 3e so to 2xlst laparotomy. ..l 34 .13 28 iAutopsy .j m H 300 30 .25 .14

No biopsy taken.

The daily dosngo administered alter the first laparotomy. "The dailydosage :nlministemd after the second laparotomy. ""Ihe prostate volumeis approximated by multiplying the three dimensions indicated.

In one study, ten dogs were used to determine the action of candicidin,the results of which are reported in Table I below.

As indicated in Table I a second surgical laparotomy was performed onfour of the ten dogs in lieu of autopsy because these four dogs weresubsequently continued 1. A process for the treatment of prostatichypertrophy in a mammal afflicted with prostatic hypertrophy whichcomprises orally administering to said mammal an effective dose fortreating prostatic hypertrophy of filipin.

2. A process for treating prostatic hypertrophy as recited in claim 10which comprises orally administering from about 1 milligram to about 100miligrams of

2. A process for treating prostatic hypertrophy as recited in claim 10which comprises orally administering from about 1 milligram to about 100miligrams of filipin per kilogram of body weight per day.
 3. A processfor treating prostatic hypertrophy in a large mammal as recited in claim12 which comprises orally administering to said mammal from about 5milligrams to about 40 milligrams of filipin per kilogram of body weightper day.